Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis.

BACKGROUND: The efficacy and safety of anti-tumor necrosis factor-α (TNF-α) monoclonal antibody therapy [adalimumab (ADA) and infliximab (IFX)] with therapeutic drug monitoring (TDM), which has been proposed for inflammatory bowel disease (IBD) patients, are still controversial. AIM: To determine the efficacy and safety of anti-TNF-α monoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions. METHODS: As of July 2023, we searched for randomized controlled trials (RCTs) and observational studies in PubMed, Embase, and the Cochrane Library to compare anti-TNF-α monoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy. Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery. RESULTS: This systematic review and meta-analysis yielded 13 studies after exclusion, and the baseline indicators were balanced. We found a significant increase in the number of patients who achieved clinical remission in the ADA [odds ratio (OR) = 1.416, 95% confidence interval (CI): 1.196-1.676] and RCT (OR = 1.393, 95%CI: 1.182-1.641) subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive (OR = 0.237, 95%CI: 0.101-0.558) and IFX + ADA (OR = 0.137, 95%CI: 0.032-0.588) subgroups, and the overall risk of adverse events was reduced (OR = 0.579, 95%CI: 0.391-0.858) according to the pairwise meta-analysis. Moreover, the network meta-analysis results suggested that patients with IBD treated with ADA (OR = 1.39, 95%CI: 1.19-1.63) were more likely to undergo TDM, especially in comparison with patients with reactive TDM (OR = 1.38, 95%CI: 1.07-1.77). CONCLUSION: Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM. We recommend proactive TDM in IBD patients who are treated with ADA.

The ADAM17 inhibitor ZLDI-8 sensitized hepatocellular carcinoma cells to sorafenib through Notch1-integrin ß-talk.

ZLDI-8 is an A disintegrin and metalloproteinase domain 17 (ADAM17) inhibitor that suppresses the shedding of Notch1 to the Notch1 intracellular domain (NICD). In previous studies, we found that ZLDI-8 was able to sensitize HCC to sorafenib, but the mechanism of action remains unclear. The sensitizing effects of ZLDI-8 were tested both in vitro and in vivo. EMT-related factors, sorafenib sensitivity-related proteins and ECM-related gene expression were assessed using immunohistochemistry, RTPCR and Western blotting. Knockdown assays were conducted to determine the relationship between the Notch and Integrin pathways. CoIP assays, nuclear and cytoplasmic fractionation and immunofluorescence colocalization were applied to explore the interaction between the Notch and Integrin pathways. Appropriate statistical analysis methods were used to assess the significance of the experimental results and to ensure the scientific validity and reliability of the experimental design. We found that ECM- and EMT-related proteins were downregulated after ZLDI-8 treatment (P<0.05). ZLDI-8 significantly downregulated Integrinß1 and Integrinß3 in HCC in vitro and in vivo (P<0.05), possibly through Foxc2-dependent regulation. Mechanistically, interfering with the expression of both Integrin-linked kinase (ILK) and the NICD may downregulate the expression of proteins targeted by sorafenib, thereby sensitizing cells to sorafenib. The retroregulation of Integrinß by ILK may occur through the interaction between the NICD and ILK and may be the result of the translocation of the complexus. Our study indicates that blocking the Notch pathway may affect Integrinß through crosstalk between the Notch1 and Integrinß/ILK signaling pathways, thus providing a potential therapeutic strategy for HCC.

Incidence of renal cell carcinoma after solid organ transplantation: a systematic review and meta-analysis.

BACKGROUND: The incidence rate of malignant tumors after solid organ transplantation is higher than the normal population. The aim of our study is to identify the risk of renal cell carcinoma (RCC) after liver, kidney, heart and lung transplantation, respectively, and suggest that transplant patients can be screened early for tumors to avoid risk. METHODS: PubMed, Embase and the Cochrane Library from their inception until August 16,2023. Retrospective and cohort studies which focus on the statistical data of standardized incidence ratios (SIRs) of RCC after solid organ transplantation (SOT) more than one year have been included and extracted. The study was registered with PROSPERO, CRD4202022343633. RESULTS: Sixteen original studies have been included for meta-analysis. Liver transplantation could increase the risk of RCC (SIR = 0.73, 95%CI: 0.53 to 0.93) with no heterogeneity(P = 0.594, I2 = 0.0%). And kidney transplantation could increase the risk of RCC(8.54, 6.68 to 10.40; 0.000,90.0%). Besides, heart and lung transplantation also could increase the risk of RCC(SIR = 0.73, 95%CI: 0.53 to 0.93; SIR = 1.61, 95%CI:0.50 to 2.71). Moreover, significance could also be found in most subgroups, especially the European group and retrospective study group. What's more, after removing studies which have a greater impact on the overall outcome in RCC rate after kidney transplantation, heterogeneity did not solve and significant different was also observed in the European group (7.15, 5.49 to 8.81; 0.000, 78.6%). CONCLUSION: Liver, kidney, heart and lung transplantation patients have an increased risk of processing RCC compared to the general population and most subgroups, especially in geographic location of European subgroup, which suggested that patients should be screened frequently after transplantation.

Comparative efficacy and safety of glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes: A network meta-analysis.

INTRODUCTION: This study aimed to evaluate the clinical efficacy and safety of 4 weekly formulations of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on glycemic control, including glycemic control, by using a network meta-analysis (NMA). METHODS: PubMed, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched from inception until June 10, 2022. Randomized clinical trials (RCTs) enrolling participants with diabetes mellitus type 2 and a follow-up of at least 12 weeks were included, for which 4 eligible GLP-1RAs Exenatide, Dulaglutide, Semaglutide, Loxenatide were compared with either each other or placebo. The primary outcome is the change of hemoglobin A1c level. Secondary outcomes including additional glycemic control indicators and adverse events (AE). Frequentist random-effect NMA were conducted for effect comparison. This meta-analysis was registered on PROSPERO, CRD42022342241. RESULTS: The NMA synthesized evidence from 12 studies covering 6213 patients and 10 GLP-1RA regimens. A pairwise comparison of glycosylated hemoglobin type A1C (HbA1c) lowering effects showed that once-weekly GLP-1 receptor agonists were significantly better than placebo, and their glucose-lowering intensity was Semaglutide 2.0mg, Semaglutide 1.0mg, Dulaglutide 4.5mg, and Semaglutide 0.5mg, Dulaglutide 3.0mg, PEX168 200ug, Dulaglutide 1.5mg, PEX168 100ug and Dulaglutide 0.75mg. The GLP-1RA regimen has a comparable safety profile for hypoglycemia. And with the exception of PEX168, all other long-acting GLP-1RA drugs had lower rates of diarrhea, nausea and vomiting than placebo. CONCLUSION: Regimens of GLP-1RAs had differential glycemic control. The efficacy and safety of Semaglutide 2.0mg in comprehensively lowering blood sugar showed the best performance.

Systematic review and meta-analysis of calcineurin inhibitors on long-term prognosis of renal transplant patients.

BACKGROUND: Existing guidelines recommend a triple immunosuppressive regimen with calcineurin inhibitors, antimetabolites, and corticosteroids for postoperative immunosuppression in renal transplant patients. However, few studies have compared cyclosporine and tacrolimus for long-term outcomes. In this study, the meta-analysis was used to compare long-term outcomes in renal transplant patients to evaluate the use of cyclosporine vs. tacrolimus. The pros and cons of suppression programs have been analyzed. METHODS: Cyclosporine, tacrolimus, and kidney transplantation, were used as search terms to retrieve relevant publications in PubMed, Embase, and The Cochrane library. Two independent researchers screened and evaluated the relevant results of each search using the RevMan5.4 program to make relevant charts for the meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were used to report dichotomous variables, while mean differences (MD) and 95% confidence intervals (CI) were used to report continuous variables. The study took tacrolimus- and cyclosporine-based maintenance immunosuppression as experimental and control groups, respectively. The graft and patient survival outcomes were followed for 5 or more years. RESULTS: Overall, thirteen studies were included in the meta-analysis, including nine randomized controlled trials and four non-randomized controlled trials. Compared with the cyclosporine group, the incidence of rejection, drug conversion, and dyslipidemia were significantly lower in the tacrolimus group. Furthermore, there was higher glomerular filtration rates and graft survival rates in the tacrolimus group than in the cyclosporine group. In contrast, there were no significant differences between the two groups in terms of patient survival, incidence of infection, hypertension and new tumors. However, the use of tacrolimus was associated with a high risk of a new onset of diabetes. CONCLUSION: The meta-analysis showed that, compared with cyclosporine, tacrolimus increases the risk of a new-onset diabetes. However, tacrolimus had higher graft survival rate and better creatinine clearance than cyclosporine.

Diagnostic accuracy and prognostic significance of Glypican-3 in hepatocellular carcinoma: A systematic review and meta-analysis.

Purpose: Glypican-3 (GPC-3) expression is abnormal in the occurrence and development of hepatocellular carcinoma (HCC). To explore whether GPC-3 has diagnostic accuracy and prognostic significance of HCC, we did a systematic review and meta-analysis. Method: PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched with keywords "GPC-3" and "HCC" and their MeSH terms from inception to July 2022. We applied the hierarchical summary receiver operating characteristic model and evaluated the diagnostic value of GPC-3 alone and combination, and the correlation between high and low GPC-3 expression on clinicopathological features and survival data in prognosis. Results: Forty-one original publications with 6,305 participants were included, with 25 of them providing data for diagnostic value and 18 records were eligible for providing prognostic value of GPC-3. GPC-3 alone got good diagnostic value in patients with HCC when compared with healthy control and moderate diagnostic value when compared with patients with cirrhosis. In addition, combination of GPC-3 + AFP and GPC-3 + GP73 got great diagnostic value in HCC versus cirrhosis groups; the combination of GPC-3 can also improve the diagnostic accuracy of biomarkers. Moreover, we discovered that overexpression of GPC-3 was more likely found in HBV infection, late tumor stage, and microvascular invasion groups and causes shorter overall survival and disease free survival, which means poor prognosis. Conclusion: GCP-3 could be used as a biomarker in HCC diagnosis and prognosis, especially in evaluated diagnostic value in combination with AFP or GP73, and in forecasting worse survival data of overexpression GPC-3. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42022351566].

Inhibition of Angiogenesis and Extracellular Matrix Remodeling: Synergistic Effect of Renin-Angiotensin System Inhibitors and Bevacizumab.

Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-ß1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs.

The transcription factor, sterol regulatory element binding protein 1 (SREBP-1), plays important roles in modulating the proliferation, metastasis, or resistance to antitumor agents by promoting cellular lipid metabolism and related cellular glucose-uptake/Warburg Effect. However, the underlying mechanism of SREBP-1 regulating the proliferation or drug-resistance in lung squamous cell carcinoma (LUSC) and the therapeutic strategies targeted to SREBP-1 in LUSC remain unclear. In this study, SREBP-1 was highly expressed in LUSC tissues, compared with the paired non-tumor tissues (the para-tumor tissues). A novel small-molecule inhibitor of SREBP-1, MSI-1 (Ma's inhibitor of SREBP-1), based on natural product monomers, was identified by screening the database of natural products. Treatment with MSI-1 suppressed the activation of SREBP-1-related pathways and the Warburg effect of LUSC cells, as indicated by decreased glucose uptake or glycolysis. Moreover, treatment of MSI-1 enhanced the sensitivity of LUSC cells to antitumor agents. The specificity of MSI-1 on SREBP-1 was confirmed by molecular docking and point-mutation of SPEBP-1. Therefore, MSI-1 improved our understanding of SREBP-1 and provided additional options for the treatment of LUSC.

What Is the Most Suitable Agent Combined With Apatinib for Transarterial Chemoembolization Treatment in Advanced Hepatocellular Carcinoma Patients? A Systematic Review and Network Meta-analysis.

Purpose: Combined therapy with transarterial chemoembolization (TACE) and apatinib is superior in therapeutic effect compared with TACE alone in patients with hepatocellular carcinoma (HCC). To determine the most suitable agent combined with apatinib for TACE treatment, we did a systematic review and network meta-analysis. Methods: Four electronic databases were searched from inception until November 2021. Randomized controlled trials (RCTs) and retrospective studies that combined therapy of TACE and apatinib (TACE+A) compared with TACE alone were included. We performed random-effect pairwise and network meta-analyses to summarize the outcomes about efficacy and safety. Results: Forty-five original studies including 3,876 patients were included. In terms of efficacy, we evaluated treatment response, 6 months overall survival (OS), 1 year OS, 6 months progression-free survival (PFS), 1 year PFS, alphafetoprotein (AFP), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor (VEGF). Significant differences always appear in TACE agent subgroups of adriamycin, platinum, and fluorouracil from both pairwise and network meta-analysis, while significant differences could also be found in apatinib dosage of 500 and >500 mg/day subgroups and in both RCT and retrospective study subgroups. From second time network analysis, compared with TACE alone, subgroups with TACE agents of oxaliplatin, cisplatin, pirarubicin, epirubicin, and 5-fluorouracil ranked front. In addition, the safety of adriamycin, platinum, and fluorouracil subgroups is acceptable. Conclusions: In conclusion, the most suitable agents in TACE combined with apatinib were adriamycin+platinum ± fluorouracil combination therapy. Systematic Review Registration: The study was registered with https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=311650, PROSPERO, CRD4202022311650.

DHW-221, a Dual PI3K/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer.

Multidrug resistance (MDR) is considered as a primary hindrance for paclitaxel failure in non-small cell lung cancer (NSCLC) patients, in which P-glycoprotein (P-gp) is overexpressed and the PI3K/Akt signaling pathway is dysregulated. Previously, we designed and synthesized DHW-221, a dual PI3K/mTOR inhibitor, which exerts a remarkable antitumor potency in NSCLC cells, but its effects and underlying mechanisms in resistant NSCLC cells remain unknown. Here, we reported for the first time that DHW-221 had favorable antiproliferative activity and suppressed cell migration and invasion in A549/Taxol cells in vitro and in vivo. Importantly, DHW-221 acted as a P-gp inhibitor via binding to P-gp, which resulted in decreased P-gp expression and function. A mechanistic study revealed that the DHW-221-induced FOXO3a nuclear translocation via Akt inhibition was involved in mitochondrial apoptosis and G0/G1 cell cycle arrest only in A549/Taxol cells and not in A549 cells. Interestingly, we observed that high-concentration DHW-221 reinforced the pro-paraptotic effect via stimulating endoplasmic reticulum (ER) stress and the mitogen-activated protein kinase (MAPK) pathway. Additionally, intragastrically administrated DHW-221 generated superior potency without obvious toxicity via FOXO3a nuclear translocation in an orthotopic A549/Taxol tumor mouse model. In conclusion, these results demonstrated that DHW-221, as a novel P-gp inhibitor, represents a prospective therapeutic candidate to overcome MDR in Taxol-resistant NSCLC treatment.

An integrated multi-omics approach revealed the regulation of melatonin on age-dependent mitochondrial function impair and lipid dyshomeostasis in mice hippocampus.

Melatonin can improve mitochondrial dysfunction associated with the aging process by removing active oxygen, as well as inhibiting lipid peroxidation to maintain biofilm fluidity and resist free radical attack. However, there is poor understanding of the effect of melatonin on age-dependent mitochondrial function and lipid profile changes in brain. In this study, we investigated the energy metabolism of the whole body and brain of mice at 9 months, 13 months, and 25 months of continuous gastric administration of 3 mg/kg/d melatonin once per day morning for two months. In addition, we performed transcriptomic, proteomic and lipidomic analysis in the hippocampus of mice at different ages. Proteomics showed that melatonin regulated mitochondrial electron transport and leucine degradation in mouse hippocampus. Lipomics suggested that the long-chain unsaturated glycerol phospholipids in mouse hippocampus increased in an age-dependent manner, while ceramide and glycerol phospholipids decreased significantly in hippocampus of mouse chronically exposed to melatonin. The combined analysis of proteome and liposome demonstrated that Mpst, Ccsap, Hdhd5, Rpl5 and Flna were the key proteins of the network which involved in the regulation of numerous lipids. Furthermore, ultrastructure observation results illustrated that melatonin could improve the damaged mitochondrial and morphologies of 25-month-old mice hippocampus. In conclusion, we describe a mechanism that age-dependent up-regulation of long-chain unsaturated lipids is a driving risk factor for mitochondrial damage and this effect could be reversed by chronic supplement of low-dose melatonin.

Efficacy and safety of donepezil for mild cognitive impairment: A systematic review and meta-analysis.

OBJECTIVE: This study intends to systematically evaluate the efficacy and safety of donepezil for improving cognitive function in patients with mild cognitive impairment (MCI), and to provide evidence-based foundation for donepezil in MCI treatment. METHODS: We searched in PubMed, Embase, Cochrane Library, Clinical trials.gov, Web of Science, CQVIP, and CNKI databases, and then we summarized the interventional and observational studies on the use of donepezil for improving the cognitive function of MCI patients. The literature was collected according to the inclusion criteria for data extraction. We evaluated the quality of the selected literature and used Stata 15.0 for meta-analysis. RESULTS: A total of 12 randomized controlled trials (RCTs) and 5 non-randomized concurrent controlled trials (CCTs) were included, and a total of 2847 patients were included. In terms of efficacy, meta-analysis showed that donepezil could significantly improve the MMSE (SMD: 0.85, 95%CI: 0.40-1.31) and MoCA (SMD: 1.88, 95%CI: 0.32-3.45) scores of MCI patients. Donepezil could not significantly reduce ADAS-cog score, nor could it significantly delay disease progression. The quality of the evidence was low overall. In terms of safety, donepezil could significantly increase the risk of adverse reactions such as nausea, vomiting, diarrhea in patients with MCI. CONCLUSION: Donepezil can improve the cognitive function of MCI patients to a certain extent. However, there is no trend of significantly delaying the progression of the disease, and it is easy to lead to the occurrence of adverse reactions.

miR-140-3p enhances the sensitivity of LUAD cells to antitumor agents by targeting the ADAM10/Notch pathway.

Background: The Notch pathway, which is related to the drug-resistance of lung adenocarcinoma (LUAD) type of non-small cell lung cancer (NSCLC) cells, is activated by cleavage of Notch proteins mediated by ADAMs, ADAM10 or ADAM17. Methods: In the present study, our results demonstrated that of these two ADAMs, the expression of ADAM10 in clinical samples of the LUAD type of NSCLC was much higher than that of ADAM17, while miR-140-3p - an miRNA that could target ADAM10 - was identified by an online tool: miRDB (miRNA database). The detail function and mechanism of miR-140-3p in regulating the sensitivity of NSCLC cells to antitumor drugs was systematically explored in vitro and in vivo. Results: In A549, a typical NSCLC LUAD cell line, miR-140-3p decreased ADAM10 expression and repressed activation of the Notch pathway by repressing cleavage of Notch proteins. The expression of miR-140-3p was negatively related to ADAM10 in clinical specimens. Nucleocytoplasmic separation/subfraction assays showed that miR-140-3p was able to inhibit the cleavage of Notch protein, and led to the accumulation of Notch intracellular domains (NICD) in the nucleus. Overexpression of miR-140-3p enhanced the sensitivity of A549 cells to antitumor agents by targeting the 3'UTR region of ADAM10 mRNA in both cultured cells and in vivo models. Conclusion: ADAM10 plays a major role in LUAD, and miR-140-3p acts on ADAM10 and inhibits its expression and the cleavage of Notch protein, leading to the inhibition the activity of the Notch pathway, and ultimately upregulating LUAD cell sensitivity to anti- tumor drugs.

Diagnostic accuracy and prognostic significance of osteopontin in liver cirrhosis and hepatocellular carcinoma: a Meta-analysis.

OBJECTIVE: At present, there is no definite suggestion about effective tumour biomarkers for the diagnostic accuracy and prognostic significance of hepatocellular carcinoma (HCC) and liver cirrhosis (LC). The aim of our research was to determine the value of the tumour biomarker osteopontin (OPN), which is encoded by the Spp1 gene, in the diagnosis, prognosis and development of HCC and LC through meta-analysis. METHODS: A systematic literature search was performed in the PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure electronic databases up to March 2021. Studies evaluating the diagnostic and/or prognostic value of OPN in HCC and/or LC were included. RESULTS: From the systematic search, 35 studies including 9150 participants were eligible, 25 of which provided data on the diagnostic value of OPN overexpression, while 15 studies provided data on the prognostic value. OPN had high diagnostic accuracy in both HCC and LC patients compared with healthy controls, and the diagnostic efficiency was increased by the biomarker combination OPN + AFP. CONCLUSIONS: OPN may be adopted as a promising predictive tumour biomarker for the diagnosis and prognosis of HCC and LC and may be a potential therapeutic target.

Pharmacokinetics, tissue distribution, and antitumor activity of a novel compound, NY-2, in non-small cell lung cancer.

Introduction: ZLDI-8, which has a relatively strong antitumor activity, is an inhibitor of ADAM-17 and acts on the Notch signaling pathway. To further optimize its structure and improve its activity, a series of derivatives of ZLDI-8 was synthesized. NY-2 was the most effective derivative based on preliminary activity screening in vitro, with no obvious toxicity after administration in vivo. Method: The study aimed to determine the pharmacokinetics, tissue distribution, hepatotoxicity, nephrotoxicity, and antitumor activity of compound NY-2 on non-small cell lung cancer (NSCLC) in vitro and in vivo. Results: The in vivo pharmacokinetics parameters of NY-2 were better than those of ZLDI-8. The tissue distribution analysis showed that tail vein injection of 6 mg/kg of NY-2 in rats resulted in the highest concentration in the lung, so we hypothesized that NY-2 might be effective in the treatment of non-small cell lung cancer. In vitro assays showed that NY-2 significantly inhibited tumor colony formation, invasion, and migration and increased LDH activity and apoptosis in a concentration-dependent manner in non-small cell lung cancer cells. NY-2 also inhibited the formation of lung metastases without significant toxicity to major organs in nude mice. Conclusion: Compared with the parent compound, ZLDI-8, the activity and safety of NY-2 were higher. NY-2 acts on ADAM17 and simultaneously affects the downstream Notch1 and integrinß1 signaling pathways resulting in antitumor activity. Thus, NY-2 could be a potential antitumor agent, inhibiting the organization and development of non-small cell lung cancer.

The Effect of Video Game-Based Interventions on Performance and Cognitive Function in Older Adults: Bayesian Network Meta-analysis.

BACKGROUND: The decline in performance of older people includes balance function, physical function, and fear of falling and depression. General cognitive function decline is described in terms of processing speed, working memory, attention, and executive functioning, and video game interventions may be effective. OBJECTIVE: This study evaluates the effect of video game interventions on performance and cognitive function in older participants in terms of 6 indicators: balance function, executive function, general cognitive function, physical function, processing speed, and fear of falling and depression. METHODS: Electronic databases were searched for studies from inception to June 30, 2020. Randomized controlled trials and case-controlled trials comparing video game interventions versus nonvideo game control in terms of performance and cognitive function outcomes were incorporated into a Bayesian network meta-analysis. All data were continuous variables. RESULTS: In total, 47 studies (3244 participants) were included. In pairwise meta-analysis, compared with nonvideo game control, video game interventions improved processing speed, general cognitive function, and depression scores. In the Bayesian network meta-analysis, interventions with video games improved balance function time (standardized mean difference [SMD] -3.34, 95% credible interval [CrI] -5.54 to -2.56), the cognitive function score (SMD 1.23, 95% CrI 0.82-1.86), processing speed time (SMD -0.29, 95% CrI -0.49 to -0.08), and processing speed number (SMD 0.72, 95% CrI 0.36-1.09), similar to the pairwise meta-analysis. Interventions with video games with strong visual senses and good interactivity ranked first, and these might be more beneficial for the elderly. CONCLUSIONS: Our comprehensive Bayesian network meta-analysis provides evidence that video game interventions could be considered for the elderly for improving performance and cognitive function, especially general cognitive scores and processing speed. Games with better interactivity and visual stimulation have better curative effects. Based on the available evidence, we recommend video game interventions for the elderly. TRIAL REGISTRATION: PROSPERO CRD42020197158; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=197158.

Could Camrelizumab Plus Chemotherapy Improve Clinical Outcomes in Advanced Malignancy? A Systematic Review and Network Meta-Analysis.

PURPOSE: Camrelizumab is a novel programmed cell death 1 (PD-1) inhibitor. To determine the efficacy and safety of the combination treatment of camrelizumab+chemotherapy and camrelizumab monotherapy, and determine which is the most suitable malignancy type to be treated with camrelizumab, we performed a systematic review and network meta-analysis. METHODS: We searched PubMed, Embase, and the Cochrane Library for published clinical trials from database inception until April 2021. Studies that compared camrelizumab+chemotherapy and camrelizumab monotherapy in patients with advanced malignancy were included. We estimated odds ratios (ORs) with credible intervals (CIs) using network meta-analysis with random effects. RESULTS: We included four clinical trials with 946 advanced malignancy patients. In terms of the efficacy evaluation of the objective response rate and progression-free survival, camrelizumab treatment for Hodgkin lymphoma (HL), camrelizumab treatment for esophageal squamous cell carcinoma (OSCC), and camrelizumab+chemo treatment for HL always ranked first. In terms of safety evaluation from leukocytopenia, hypothyroidism, and asthenia, camrelizumab treatment for OSCC and chemo always ranked first. This study was registered with PROSPERO, number CRD42021249193. CONCLUSIONS: Patients with advanced OSCC should be treated with camrelizumab. Patients with severely relapsed/refractory HL could use camrelizuma+chemo for combination treatment when they can tolerate adverse reactions. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249193, PROSPERO (identifier, CRD42021249193).

Enhancing the flow field in parallel spiral-flow column photobioreactor to improve CO2 fixation with Spirulina sp.

A parallel spiral-flow column photobioreactor (PSCP) composed of eight spiral-flow columns, and two pipe headers was designed for scale-up cultivation of microalgae to capture CO2. To solve the disturbance of spiral flow fields among parallel columns, computational fluid dynamics (CFD) simulation was used to optimize the main structural parameters, such as the number and the height of microalgae solution outlet (MSO), to improve flow field structure and enhance the cells' light/dark cycle. The horizontal velocity in the direction of optical path and the turbulent kinetic energy (TKE) reached the peak values of 0.214 m/s and 5.28 m2/s2 when MSO number was four and MSO height was 1.05 m. Meanwhile, the disturbance of the spiral flow field among parallel columns are minimum, and microalgae light/dark cycle frequency was 33.3% higher than that of conventional bubble column photobioreactor. Therefore, the biomass yield and CO2 fixation rate of microalgae increased by 81.5% and 100.5%, respectively.

Does coffee, tea and caffeine consumption reduce the risk of incident breast cancer? A systematic review and network meta-analysis.

OBJECTIVE: We aimed to evaluate the association between coffee and/or tea consumption and breast cancer (BC) risk among premenopausal and postmenopausal women and to conduct a network meta-analysis. DESIGN: Systematic review and network meta-analysis. SETTING: We conducted a systematic review of electronic publications in the last 30 years to identify case-control studies or prospective cohort studies that evaluated the effects of coffee and tea intake. RESULTS: Forty-five studies that included more than 3 323 288 participants were eligible for analysis. Network meta-analysis was performed to determine the effects of coffee and/or tea consumption on reducing BC risk in a dose-dependent manner and differences in coffee/tea type, menopause status, hormone receptor and the BMI in subgroup and meta-regression analyses. According to the first pairwise meta-analysis, low-dose coffee intake and high-dose tea intake may exhibit efficacy in preventing ER(estrogen receptor)- BC, particularly in postmenopausal women. Then, we performed another pairwise and network meta-analysis and determined that the recommended daily doses were 2-3 cups/d of coffee or ≥5 cups/d of tea, which contained a high concentration of caffeine, particularly in postmenopausal women. CONCLUSIONS: Coffee and tea consumption is not associated with a reduction in the overall BC risk in postmenopausal women and is associated with a potentially lower risk of ER- BC. And the highest recommended dose is 2-3 cups of coffee/d or ≥5 cups of tea/d. They are potentially useful dietary protectants for preventing BC.

Rhamnetin decelerates the elimination and enhances the antitumor effect of the molecular-targeting agent sorafenib in hepatocellular carcinoma cells via the miR-148a/PXR axis.

The pregnane X receptor (PXR) mediates the resistance of sorafenib in hepatocellular carcinoma (HCC) by promoting the clearance or elimination of sorafenib via the drug resistance-related downstream genes of the PXR. Previously, we revealed that rhamnetin (a flavonoid functioning as an inhibitor of sirtuin (Sirt)1) could inhibit expression of the downstream gene of the PXR: multidrug resistance 1 (mdr-1). However, how rhamnetin regulates the PXR pathway in HCC cells is not known. Here, we demonstrated that rhamnetin decelerated elimination of the molecular-targeting agent sorafenib in HCC cells via the microRNA (miR)-148a/PXR axis. Rhamnetin treatment decreased expression of the drug resistance-related downstream genes of PXR (cyp3a4 [cytochrome P-450] or mdr-1 [multi-drug resistance 1]), which mediate the metabolism or elimination of sorafenib in HCC cells. Mechanistically, rhamnetin increased expression of miR-148a (which is tumor-suppressive) in a P53-dependent manner, leading to inhibition of PXR expression and decrease in expression of its downstream genes. Rhamnetin enhanced miRNA-148a transcription by repressing Sirt1 activation to enhance acetylation at residue-373 of P53. Rhamnetin treatment decelerated the metabolic clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. Our results suggest that rhamnetin could be a potential agent for overcoming sorafenib resistance in HCC treatment.